The cytoplasmic tail dileucine motif LL572 determines the glycosylation pattern of membrane-type 1 matrix metalloproteinase.
Membrane-type 1 matrix metalloproteinase (MT1-MMP; MMP-14) drives fundamental physiological and pathological processes, due to its ability to process a broad spectrum of substrates. Because subtle changes in its activity can produce profound physiological effects, MT1-MMP is tightly regulated. Currently, many aspects of this regulation remain to be elucidated. It has recently been discovered that O-linked glycosylation defines the substrate spectrum of MT1-MMP. We hypothesized that a mutual interdependency exists between MT1-MMP trafficking and glycosylation. Lectin precipitation, metabolic labeling, enzymatic deglycosylation, and site-directed mutagenesis studies demonstrate that the LL(572) motif in the cytoplasmic tail of MT1-MMP influences the composition of the complex O-linked carbohydrates attached to the hinge region of the protein. This influence appears to be independent from major effects on cell surface trafficking. MT1-MMP undergoes extensive processing after its synthesis. The origins and the molecular characters of its multiple forms are incompletely understood. Here, we develop and present a model for the sequential, post-translational processing of MT1-MMP that defines stages in the post-synthetic pathway pursued by the protein.
Ludwig
Thomas
T
German Cancer Research Center Heidelberg, Microenvironment of Tumor Cell Invasion, Im Neuenheimer Feld 267, Heidelberg 69120, Germany. t.ludwig@dkfz.de
Theissen
Sarah M
SM
Morton
Michael J
MJ
Caplan
Michael J
MJ
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics; D002522:Chlorocebus aethiops; D006031:Glycosylation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D046188:Protein Modification, Translational / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D013379:Substrate Specificity / Q000502:physiology
D007527:Isoenzymes; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14